Insulin resistance is defined as a state associated with low or impaired biologic response to insulin. Insulin resistance may include altered sensitivity to any biologic action of insulin, including effects on carbohydrate, lipid or protein metabolism. Further, insulin action in enhancing nitric oxide release and vascular smooth muscle relaxation may be impaired in an insulin resistant patient.
The best studied disease associated with insulin resistance is Type 2 diabetes. Type 2 diabetes, previously called adult-onset diabetes or non-insulin dependent diabetes mellitus type (NIDDM), results principally from one of two defects. One is that .beta. islet cells are defective in secreting sufficient insulin in response to an elevation in blood glucose. The other is that target cells, such as adipocytes and skeletal muscle cells, do not respond to an increase in insulin by elevating glucose transport. Interestingly, the insulin receptors and at least some parts of the insulin signaling pathways in these patients suffering Type 2 diabetes appear to be normal. Patients with diabetes suffer from the effects of prolonged elevation of blood glucose levels.
There have been extensive studies to identify the biochemical and genetic factors leading to Type 2 diabetes and impaired glucose tolerance. National Diabetes Data Group, Diabetes In America 2nd Ed. NIH publication No. 95-1468, 1995. Most investigators believe that the initial biochemical defect is the reduction of insulin mediated glucose uptake, which worsens with age and adiposity. However, Type 2 diabetes develops only upon some reduction in insulin secretion. This defect is in the .beta. cells, and it is specific for the reduction of the glucose-induced insulin secretion. Such a defect may occur at any age, but usually after the age of 35 years. Moreover, glucose itself can lead to a further impairment of insulin action.
The prevalence of diabetes is rapidly increasing. Nearly 6% of the general population has diabetes of which 95% have Type 2 diabetes. The rate is even higher in minorities and in people over the age of 65 (10.5%). Data in 1992 showed that $1 in every $7 spent in health care in this country was spent on the care for people with diabetes. New treatments to control the above-detailed parameters will improve the health care of people with diabetes, and any treatment that reduces the rate of diabetes development or mitigates the rate at which diabetic patients develop complications will advance the treatment options available to the diabetic. Current treatments, however, are insufficient.
Insulin resistance is also associated with conditions other than Type 2 diabetes, however. Reduced insulin action is also associated with other factors, including certain drugs, like corticosteroids, growth hormone, thiazide diuretics, stress hormones, increased fat intake, and cytokines, such as tumor necrosis factor. Insulin resistance is also common in all of the people with simple obesity and impaired glucose tolerance (IGT), as well as a substantial percentage of the people with essential hypertension and atherosclerosis. A syndrome associating insulin resistance with increased cardiovascular disease has also been described.
"Syndrome X" is a clustering of abnormalities, including dyslipidemia, hypertension, coronary artery disease, central obesity, hyperuricemia, impaired fibrinolysis, polycystic ovary syndrome (PCOS) in women, glucose tolerance and insulin resistance. Reaven, DIABETES MELLITUS, pp. 509-19, Le Roth et al, eds. (1996). Moreover, fasting hyperinsulinemia (a marker of insulin resistance) is associated with cardiovascular disease and, like high triglyceride levels, hyperinsulinemia is an independent risk factor in comoary artery disease, even in non-diabetic subjects. Despres et. al. New Engl. J. Med. 334: 952-57 (1996). Studies suggest that decreasing insulin resistance is helpful treating the above-mentioned conditions, including PCOS (Dunaif et al., J. Clin. Enocrinol. Metab. 81: 3299-3306 (1996) and IGT (Antonucci et al., 83: 1818-20 (1998)).
Insulin resistance is also associated with low high density lipoprotein cholesterol and a shift toward smaller, denser, low density lipoprotein cholesterol particles, which are more atherogenic. Insulin resistance is also associated with hypertension, particularly in whites. The link of insulin resistance to cardiovascular disease is further substantiated by epidemiology (Haffner et al., Am. J. Med. 103: 152-62 (1997); Howard et al., Circulation 93: 1809-17 (1996)), by studies evaluating its role in blood pressure regulation (Ferranni et al., New Engl. J. Med. 317: 350-57 (1987)), and by the observation that drugs that improved insulin action can decrease the proportion of small dense low density lipoprotein particles in obese subjects (Tack et al., Diabetes Care 21: 796-99 (1998). Other studies show that insulin can potentiate vascular disease by reducing fibrinolysis (Sobel, Circulation 93: 1613-15 (1996).
In view of the foregoing, it is apparent that a need exists in the art of for new and improved compositions and therapeutics methods that ameliorate insulin resistance and are thus useful in treating the foregoing conditions.